Targeting Thymidylate Synthase and tRNA-Derived Non-Coding RNAs Improves Therapeutic Sensitivity in Colorectal Cancer
Changwon Yang,
Jisoo Song,
Sunwoo Park,
Jiyeon Ham,
Wonhyoung Park,
Hahyun Park,
Garam An,
Taeyeon Hong,
Hee Seung Kim,
Gwonhwa Song,
Whasun Lim
Affiliations
Changwon Yang
Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
Jisoo Song
Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Korea
Sunwoo Park
Department of Plant & Biomaterials Science, Gyeongsang National University, Jinju 52725, Korea
Jiyeon Ham
Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
Wonhyoung Park
Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
Hahyun Park
Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
Garam An
Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
Taeyeon Hong
Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Korea
Hee Seung Kim
Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul 03080, Korea
Gwonhwa Song
Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
Whasun Lim
Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Korea
Some colorectal cancer (CRC) patients are resistant to 5-fluorouracil (5-FU), and high expression levels of thymidylate synthase (TS) contribute to this resistance. This study investigated whether quercetin, a representative polyphenol compound, could enhance the effect of 5-FU in CRC cells. Quercetin suppressed TS levels that were increased by 5-FU in CRC cells and promoted the expression of p53. Quercetin also induced intracellular and mitochondrial reactive oxygen species (ROS) production and Ca2+ dysregulation in a 5-FU-independent pathway in CRC cells. Furthermore, quercetin decreased mitochondrial membrane potential in CRC cells and inhibited mitochondrial respiration. Moreover, quercetin regulated the expression of specific tiRNAs, including tiRNAHisGTG, and transfection of a tiRNAHisGTG mimic further enhanced the apoptotic effect of quercetin in CRC cells. An enhanced sensitivity to 5-FU was also confirmed in colitis-associated CRC mice treated with quercetin. The treatment of quercetin decreased survival rates of the CRC mouse model, with reductions in the number of tumors and in the disease activity index. Also, quercetin suppressed TS and PCNA protein expression in the distal colon tissue of CRC mice. These results suggest that quercetin has the potential to be used as an adjuvant with 5-FU for the treatment of CRC.
